TRANSDEATH Sintesi della relazione

Final Report Summary - TRANSDEATH (Programmed cell death across the eukaryotic kingdom)

Programmed cell death (PCD) is normally invoked during development and immunity, but inappropriate PCD is associated with pathologies including cancer and degenerative diseases. Genes controlling one type of PCD (apoptosis) were first identified in the worm model C. elegans. Biomedical research has established related mammalian apoptotic pathways. However, other conserved PCD types exist in animal and non-animal cells. The TRANSDEATH project focused on cellular and molecular events in these lesser known models to broaden the experimental net to catch PCD regulators by comparative research on diverse organisms. The main approach was across the eukaryotic kingdoms, aimed at understanding these types of cell death in humans. TRANSDEATH thus produced knowledge on genes and biochemical processes that regulate PCD in different organisms.

Although clear homologs of the apoptotic proteins are not found in plants and lower eukaryotes, comparative analysis of their conserved domains conserved indicates that they existed in the common ancestor of animals, plants, and fungi. These ancient domains were, and in some cases still are, components of ancestral signalling pathways for responses to pathogens and stresses including starvation and DNA damage. TRANSDEATH sought to understand the mechanistic relations between extant PCD programs in different organisms. For example, plant leaves senesce at the end of growth seasons. How is this developmental form of PCD related to the more rapid PCD induced during the plant hypersensitive response to pathogens? Similarly, how may these forms of PCD be related to autophagic processes in animals or in fungi and moulds that induce PCD during incompatible mating interactions, or during the development of reproductive structures? Lastly, how are apoptosis or autophagy related to PCD in unicellular yeasts in which it may have evolved as an altruistic defence of clonal populations?

The TRANSDEATH work plan defined, phenomenologically and molecularly, distinct types of cell death using models appropriate for each type of death. It then extracted, from a comparison between models and analyses of phylogenetic conservation throughout the models, the core mechanism(s) of these types of death. A main focus was on events in the less studied cell death types that are non-apoptotic. These mechanisms were then used to understand corresponding types of cell death in mammals, in particular humans.

In summary, the partners met the general objectives of the project. Specific results within the workpackages are best assessed by referral to the 137 publications in internationally reviewed, scientific journals and 7 solicited book chapters authored by the partners. A partial overview of the results and their relation to the development of our understanding of programmed cell death is also presented in multiple articles by the partners in a special issue of Seminars in Cancer Biology edited by partner 3B (Seminars in Cancer Biology 2007 Apr 17(2)).